The present invention relates to spiro[6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones] which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones and method for preventing, abating, or otherwise controlling enzymes which are understood to be the active components responsible for the herein described disease states.
Interleukin-1 (IL-1) and Tumor Necrosis Factor-xcex1 (TNF-xcex1) are among the important biological substances known collectively as xe2x80x9ccytokines.xe2x80x9d These molecules are understood to mediate the inflammatory response associated with the immunological recognition of infectious agents.
These pro-inflammatory cytokines are suggested as an important mediators in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia, and therefore responsible for the progression and manifestation of human disease states.
There is therefore a long felt need for compounds and pharmaceutical compositions which comprise compounds, which can block, abate, control, mitigate, or prevent the release of cytokines from cells which produce them.
The present invention meets the aforementioned needs in that it has been surprisingly found that certain spiro-bicyclic pyrazolones and derivatives thereof are effective for inhibiting release of inflammatory cytokines, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF) from cells and thereby preventing, abating, or otherwise controlling enzymes which are proposed to be the active components responsible for the herein described disease states.
The first aspect of the present invention relates to compounds, including all enantiomeric and diastereomeric forms and pharmaceutically acceptable salts thereof, said compounds having the formula: 
wherein R is:
a) xe2x80x94O[CH2]kR3; or
b)xe2x80x94NR4aR4b;
R3 is substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; the index k is from 0 to 5;
R4a and R4b are each independently:
a) hydrogen; or
b) xe2x80x94[C(R5aR5b)2]mR6;
each R5a and R5b are independently hydrogen, xe2x80x94OR7, xe2x80x94N(R7)2, xe2x80x94CO2R7, xe2x80x94CON(R7)2; C1-C4 linear, branched, or cyclic alkyl, and mixtures thereof; R6 is hydrogen, R7, xe2x80x94N(R7)2, xe2x80x94CO2R7, xe2x80x94CON(R7)2; substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, or C1-C4 alkyl; the index m is from 0 to 5;
R1 is:
a) substituted or unsubstituted aryl; or
b) substituted or unsubstituted heteroaryl;
at least two R2 units of one xe2x80x94[C(R2)2]xe2x80x94 ring unit are taken together to form a spirocyclic ring having from 4 to 7 atoms, the balance of the R2 units are independently selected from the group consisting of:
a) hydrogen;
b) xe2x80x94(CH2)kO(CH2)jR8;
c) xe2x80x94(CH2)jNR9aR9b;
d) xe2x80x94(CH2)jCO2R10;
e) xe2x80x94(CH2)jOCO2R10 
f) xe2x80x94(CH2)jCON(R10)2; and
g) two R2 units can be taken together to form a carbonyl unit;
R8, R9a, R9b, and R10 are each independently hydrogen, C1-C4 alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R10 units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; the index k is from 0 to 5; the index n is from 3 to 5.
Another aspect of the present invention relates to pharmaceutical compositions which can deliver the compounds of the present invention to a human or higher mammal, said compositions comprising:
a) an effective amount of one or more of the compounds according to the present invention; and
b) one or more pharmaceutically acceptable excipients.
A further aspect of the present invention relates to methods for controlling one or more inflammatory cytokine mediated or inflammatory cytokine modulated mammalian diseases or conditions, said method comprising the step of administering to a human or higher mammal and effective amount of a composition comprising one or more of the compounds according to the present invention.
These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (xc2x0C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.